Pharmacokinetic Investigations of Oral Amodiaquine in Ghanaian Children: A Case Study of Suntreso Government Hospital, Kumasi.
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Date
2009-07-11
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Abstract
With the emergence or development of resistance to anti – malarial drugs, the World
Health Organization (W.H.O.) now recommends treatment with one of several
artimisinin based combination therapies (ACT’s) which includes artesunate plus
amodiaquine. To date at least fifteen African countries including Ghana have adopted this
treatment policy for uncomplicated malaria.
Despite the extensive use of amodiaquine, (as combination therapy) in the treatment of
uncomplicated malaria, its pharmacokinetic data, especially in the Sub-Saharan African
region is limited. Therefore for optimization of its use in the country there is the urgent
need for a clear understanding of its pharmacokinetics. This study therefore seeks to
investigate the pharmacokinetics of oral amodiaquine, following administration of the
suspension form of the drug to Ghanaian children with uncomplicated malaria. The
analysis was based only on urine data.
Fifteen Ghanaian children with uncomplicated malaria, but without any history of liver or
kidney diseases and of ages between 8 and 12 years, were made to participate in the
study. These subjects or patients who were selected from the Suntreso Government
Hospital, were given oral doses of amodiaquine suspension, 10 mg/kg body weight in a
single dose study.
Urine samples were serially collected via a non-invasive approach for a period of 30 hrs.
Urine concentrations of the drug, in the unmetabolized form were determined. The urine
amodiaquine concentration was determined by liquid – liquid extraction (L.L.E.),
followed by ultraviolet (U.V) Spectroscopy analysis. The Pharmacokinetic parameters of
the drug which were investigated include, fe, kel, t 1/2, ke, km, ka, and t 1/2a. Statistically,
the Pharmacokinetic parameter values were estimated at a probability level of p = 0.05.
Extremely low fe values were obtained with a range of between 0.0035 and 0.0083;
mean, (0.0059 +/- 0.0011). The estimated overall elimination rate constant kel, ranged
from 0.1283 to 0.1823 hr -1; mean, (0.1553 +/- 0.0126 hr -1). The corresponding
elimination half – life (t 1/2) range was between 4.0845 and 5.6647 hrs; mean, (4.8746 +/-
0.3691 hrs.).The metabolic rate constant km, ranged from 0.1280 to 0.1816 hr -1; mean,
(0.1548 +/- 0.0125 hr -1.), with a corresponding excretion rate constant ke, range of
between 0.0004 and 0.0012 hr -1; mean, (0.0008 +/- 0.0002 hr -1.).
An absorption rate constant ka, range values of between 0.3586 and 0.5418 hr -1; mean,
( 0.4502 +/- 0.0428 hr -1.) were obtained. The corresponding absorption half-life (t ½ a)
values estimated were; range 1.4129 to 2.0271hrs.; mean, (1.7200 +/- 0.1435 hrs).
The study confirms orally administered amodiaquine’s rapid absorption as well as
extensive hepatic first- pass metabolic effect as published in literature. Statistically, the
pharmacokinetic parameters estimated were similar to those published in literature in
healthy Caucasian adults as there was no significant difference between the two data. It
appears from this observation that, age does not seem to exert any influence on the
pharmacokinetics of oral amodiaquine.
However, further statistical analyses revealed high significant differences in the
pharmacokinetics of the drug between the study data of Ghanaian children and Zambian
adults. The mean half life value and thereby the average plasma concentration at steady
state of the drug was significantly higher in the Ghanaian children sub population than in
the Zambian adults. This implies, perhaps, the need for separate dosing regimen of oral
amodiaquine in these two sub populations. The currently available dosing regimen of the
drug in the country, (which is based on pharmacokinetic studies in East African subjects)
upon recommendations from the World Health Organization may thereby be
inappropriate. Therefore to optimize oral amodiaquine therapy in the country there may
be the need for its dosage regimen adjustment, probably in the downward trend.
However, further pharmacokinetic studies based on both urine and plasma data as well
as larger study sample sizes across board in Ghanaians, are needed to effect optimization
of the dosage regimen of amodiaquine.
Description
A thesis submitted to the Department of Pharmaceutics,Kwame Nkrumah University of Science and Technology in partial fulfillment of the requirements for the degree of MASTER OF PHARMACOLOGY
(PHARMACEUTICS).